Polychlorinated biphenyls (PCBs) interact with drug metabolism in vivo

Archives of Toxicology, vol. 99, pp. 4423–4437

Abstract

Abstract Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that interfere with xenobiotic metabolism, primarily by modulating cytochrome P450 (CYP) enzymes. However, their pharmacokinetic consequences in exposed individuals remain poorly defined. Here, we investigated the impact of PCB exposure on CYP enzyme activity using a combined clinical pharmacokinetic and in vitro mechanistic approach. Ten occupationally PCB-exposed individuals from the German HELPcB cohort and ten controls received a CYP phenotyping cocktail to assess enzyme function (Clinical Trial Registry: DRKS00028922). Plasma drug and metabolite concentrations were quantified to evaluate CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A activity, considering genetically defined metabolizer status. PCB118 exposure was significantly associated with reduced CYP1A2 activity (R2 = 0.155, t = − 2.115, p = 0.049, β = − 0.446), indicating a decrease in CYP1A2 activity with higher PCB118 levels. This was further supported by in vitro assays demonstrating dose-dependent inhibition. In addition, PCB74 exposure showed a trend toward increased CYP2C9 activity, suggesting a potential inductive effect. Mechanistic studies revealed that PCB118 acts as both an inhibitor and a substrate of CYP1A2, generating reactive arene oxide intermediates that may contribute to mechanism-based inhibition. These findings challenge the traditional view of PCBs as merely chronic toxicants, showing that they can acutely alter drug metabolism and potentially impact drug efficacy and safety. Given the widespread presence of PCBs and other persistent organic pollutants, these results highlight the need to integrate environmental toxicant exposure into pharmacokinetic models to optimize drug therapy and minimize adverse effects.

Authors 16

1. Julian Peter Müller Aachen Institute of Clinical Pharmacology

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Clinical Pharmacology, University Hospital of RWTH, 52074, Aachen, Germany

2. Jens Rengelshausen Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

3. Salah Laieb Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

4. Andrea Kaifie Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

5. André Esser Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

6. Thomas Schettgen Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

7. Jens Bertram Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

8. Julia Krabbe Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

9. Elke Schaeffeler

   University of Tübingen · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology

   Affiliation as printed

   Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, Germany

10. Jens Andreas Sarömba Aachen Institute of Clinical Pharmacology

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Clinical Pharmacology, University Hospital of RWTH, 52074, Aachen, Germany

11. Katja Susanne Just Aachen Institute of Clinical Pharmacology

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Clinical Pharmacology, University Hospital of RWTH, 52074, Aachen, Germany

12. Roman Tremmel

    University of Tübingen · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology

    Affiliation as printed

    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, Germany

13. Matthias Schwab

    University of Tübingen · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology

    Affiliation as printed

    Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany

    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, Germany

14. Julia Stingl Aachen Institute of Clinical Pharmacology

    RWTH Aachen University · Universitätsklinikum Aachen · University Hospital Heidelberg

    Affiliation as printed

    Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany

    Institute of Clinical Pharmacology, University Hospital of RWTH, 52074, Aachen, Germany

15. Thomas Kraus Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

    RWTH Aachen University

    Affiliation as printed

    Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

16. Patrick Ziegler corresponding Aachen Medical Faculty Institute for Occupational, Social and Environmental Medicine

    RWTH Aachen University

    Affiliation as printed

    Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany. pziegler@ukaachen.de